Abstract

Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

abstract = "Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.",

author = "Hamdi Mbarek and Hidenori Ochi and Yuji Urabe and Vinod Kumar and Michiaki Kubo and Naoya Hosono and Atsushi Takahashi and Yoichiro Kamatani and Daiki Miki and Hiromi Abe and Tatsuhiko Tsunoda and Naoyuki Kamatani and Kazuaki Chayama and Yusuke Nakamura and Koichi Matsuda",

T1 - A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population

AU - Mbarek, Hamdi

AU - Ochi, Hidenori

AU - Urabe, Yuji

AU - Kumar, Vinod

AU - Kubo, Michiaki

AU - Hosono, Naoya

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Miki, Daiki

AU - Abe, Hiromi

AU - Tsunoda, Tatsuhiko

AU - Kamatani, Naoyuki

AU - Chayama, Kazuaki

AU - Nakamura, Yusuke

AU - Matsuda, Koichi

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.

AB - Hepatitis B virus (HBV) infection is a major health issue worldwide which may lead to hepatic dysfunction, liver cirrhosis and hepatocellular carcinoma. To identify host genetic factors that are associated with chronic hepatitis B (CHB) susceptibility, we previously conducted a two-stage genome-wide association study (GWAS) and identified the association of HLA-DP variants with CHB in Asians; however, only 179 cases and 934 controls were genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. Here, we performed a second GWAS of 519 747 SNPs in 458 Japanese CHB cases and 2056 controls. After adjustment with the previously identified variants in the HLA-DP locus (rs9277535), we detected strong associations at 16 loci with P-value of <5 × 10 -5. We analyzed these loci in three independent Japanese cohorts (2209 CHB cases and 4440 controls) and found significant association of two SNPs (rs2856718 and rs7453920) within the HLA-DQ locus (overall P-value of 5.98 × 10 -28 and 3.99 × 10 -37). Association of CHB with SNPs rs2856718 and rs7453920 remains significant even after stratification with rs3077 and rs9277535, indicating independent effect of HLA-DQ variants on CHB susceptibility (P-value of 1.52 × 10 -21-2.38 × 10 -30). Subsequent analyses revealed DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes. These findings indicated that variants in antigen-binding regions of HLA-DP and HLA-DQ contribute to the risk of persistent HBV infection.